Axonal Oligodendrocyte Signaling in Multiple Sclerosis

多发性硬化症中的轴突少突胶质细胞信号转导

• 批准号: 6573325
• 负责人: George Henry De Vries
• 金额: $ 30.16万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573325
• 关键词: axon; biological signal transduction; cell cell interaction; cell migration; cell proliferation; growth factor receptors; laboratory rat; multiple sclerosis; myelination; neurogenesis; neurotrophic factors; oligodendroglia; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Our long-term objective is to determine the axonal factors involved in the failure to remyelinate in diseases such as multiple sclerosis (MS). In the studies proposed here, we will isolate and characterize axonal factors that control the migration, proliferation, and survival of oligodendrocyte precursor cells (OPC cells). We focus on the initial stages of developmental myelination to gain an understanding of the molecular functions and factors that lead to normal development of a myelin sheath. Then we will investigate those same functions and factors in MS brains to determine which factors are inappropriately expressed. We hypothesize that imbalances of axonal-related growth factors contribute to the failure of remyelination in MS. In Specific Aim 1 we will characterize a process by which axonal molecules are released from a membrane fraction enriched in axonal plasma membrane. We will use medium that has been conditioned with OPC cells to stimulate the axonal-enriched fraction. Western blotting will be used to characterize the nature of the axonal factors (e.g., growth factors of different types) that are released from the axonal surface membrane. We will also characterize the types of receptors that have been activated. In Specific Aim 2 we will investigate the influence of axonal factors and how axons regulate migration, proliferation, and survival of OPC cells. Preliminary studies found that solubilized factors can stimulate proliferation. Migration assays using both soluble and particulate fractions will allow us to determine whether axonal contact and/or soluble factors released from axonal membrane are responsible for initiation and cessation of migration and proliferation. Specific Aim 3 directly tests the hypothesis that the axon-oligodendrocyte balance is altered in MS. Demyelinated areas from MS brain will be analyzed for growth factor composition (both type and ratio among them) in order to understand why oligodendrocytes migrate to the demyelinated region, proliferate, but do not remyelinate the demyelinated axons. We will obtain important information about the axonal molecules that control the early events of myelination (i.e. migration, proliferation, and survival of OPC cells), which eventually will enable researchers to pinpoint areas for therapeutic intervention.

描述（由申请人提供）：我们的长期目标是确定与多发性硬化症（MS）等疾病的髓鞘再生失败相关的轴突因素。在这里提出的研究中，我们将分离和表征控制少突胶质细胞前体细胞（OPC 细胞）迁移、增殖和存活的轴突因子。我们专注于发育髓鞘形成的初始阶段，以了解导致髓鞘正常发育的分子功能和因素。然后我们将研究多发性硬化症大脑中的相同功能和因素，以确定哪些因素表达不当。我们假设轴突相关生长因子的失衡导致多发性硬化症髓鞘再生失败。在具体目标 1 中，我们将描述轴突分子从富含轴突质膜的膜部分释放的过程。我们将使用经过 OPC 细胞调节的培养基来刺激轴突富集部分。蛋白质印迹将用于表征从轴突表面膜释放的轴突因子（例如不同类型的生长因子）的性质。我们还将描述已被激活的受体的类型。在具体目标 2 中，我们将研究轴突因素的影响以及轴突如何调节 OPC 细胞的迁移、增殖和存活。初步研究发现溶解因子可以刺激增殖。使用可溶性和颗粒级分的迁移测定将使我们能够确定轴突接触和/或从轴突膜释放的可溶性因子是否负责迁移和增殖的启动和停止。具体目标 3 直接检验 MS 中轴突-少突胶质细胞平衡发生改变的假设。将分析多发性硬化症大脑脱髓鞘区域的生长因子组成（类型和比例），以了解为什么少突胶质细胞迁移到脱髓鞘区域、增殖，但不使脱髓鞘轴突髓鞘再生。我们将获得有关控制髓鞘形成早期事件（即 OPC 细胞的迁移、增殖和存活）的轴突分子的重要信息，这最终将使研究人员能够确定治疗干预的区域。